Characterization of pheromone binding proteins

描述（由申请人提供）：社会行为是进化保守和高度刻板的。特殊化学感觉气味的释放和检测通过刺激杏仁核和下丘脑的初级回路适当地调节小鼠的社会行为。虽然化学感受配体不被认为调节人类行为，但对中风和创伤受害者的研究表明，杏仁核和下丘脑中被小鼠化学感受配体激活的相同亚核在人类中也能产生类似的社会行为。在任何物种中，产生刻板行为的神经元的精确子集都是未知的。我们现在已经确定了一个蛋白质家族的31个化学感受配体，促进刻板行为。这项研究的目的是利用这种天然的化学感受配体工具箱来识别产生刻板行为的感觉受体和神经回路。我们将系统地操纵，研究和突变这个大家族的化学感受配体的个体，以比较测试，评估和推进我们对感觉神经元，神经回路和产生行为的中央核的组织的理解。1)我们将使用钙成像来分离检测这些配体的特定神经元，并通过分子分析来识别候选感觉受体。2)我们将分析和比较暴露于我们的31种配体中的每一种后大脑中的cFos活性，以识别与每种配体相关的神经代码。3)我们将通过产生嵌合体和合理的蛋白质设计来突变我们的配体，以选择性地激活感觉神经元的亚群，并研究它们产生行为的能力。我们期望在完成这些目标时，我们将朝着阐明启动先天行为的神经元代码迈出重要的一步，并使我们能够在细胞和分子水平上定义神经功能和功能障碍的潜在机制。 公共卫生相关性：这项拟议的研究与公共卫生有关，因为对产生刻板行为的神经功能的研究有望揭示进化上保守的机制，最终将增加我们对人类刻板行为产生的理解。因此，拟议中的研究与NIH的使命相关，即了解神经功能，以最终治疗精神分裂症和自闭症等功能障碍。

DESCRIPTION (provided by applicant): Social behavior is evolutionarily conserved and highly stereotypic. Emission and detection of specialized chemosensory odorants appropriately regulates mouse social behavior through primary circuits that stimulate the amygdala and hypothalamus. Though chemosensory ligands are not thought to regulate human behavior, studies from stroke and trauma victims have revealed that the same subnuclei within the amygdala and hypothalamus that are activated by chemosensory ligands in the mouse function in humans to similarly generate social behavior. The precise subsets of neurons that generate stereotyped behavior are unknown in any species. We have now identified a protein family of 31 chemosensory ligands that promote stereotypic behavior. The objective of this research is to use this natural toolbox of chemosensory ligands to identify sensory receptors and neural circuits that generate stereotyped behavior. We will systematically manipulate, study, and mutate individuals of this large family of chemosensory ligands to comparatively test, evaluate, and advance our understanding of the organization of the sensory neurons, neural circuits, and central nuclei that generate behavior. 1) We will use calcium imaging to isolate specific neurons that detect these ligands and molecular analysis to identify candidate sensory receptors. 2) We will analyze and compare cFos activity in the brain following exposure each of our 31 ligands in order to identify the neural code associated with each ligand. 3) We will mutate our ligands through the generation of chimeras and rational protein design to selectively activate subsets of sensory neurons and investigate their ability to generate behavior. We expect that at the completion of these aims we will have made important steps towards elucidating the neuronal code that initiates innate behavior and enable us to define at the cellular and molecular level, underlying mechanisms of neural function and dysfunction. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because studies of the neural function that generates stereotyped behavior are expected to reveal evolutionarily conserved mechanisms that will ultimately increase our understanding of the generation of stereotyped behavior in humans. Thus, the proposed research is relevant to the NIH's mission to understand neural function in order to ultimately treat dysfunction such as schizophrenia and autism disorders.